Method of preparing biologically active formulations

ABSTRACT

The invention provides pellet for use as a core for a pharmaceutical dosage form having an inner and an outer zone where the inner zone includes a biologically active agent and said outer zone includes a layer formed by applying a substantially dry, free flowing inert powder which forms a non-tacky surface when placed in contact with water. The invention also provides a process for making pharmaceutical pellets where the core or at least one a layer on the core is formed by (a) contacting powder particles, adhering them to each other and compacting the adhered pellets by a rolling movement, wherein the degree of densification is controlled by the rolling movement; and (b) feeding a sufficient amount of a substantially dry, free flowing inert powder which forms a non-tacky surface when placed in contact with water to provide on said particles an outer zone including a layer formed from said substantially dry, free flowing inert powder.

The present application is a divisional of U.S. patent application Ser.No. 10/728,196 filed on Dec. 4, 2003, which claims priority from U.S.Provisional Application Ser. No. 60/432,353 filed Dec. 10, 2002, thedisclosures of which are incorporated herein by reference in theirentirety.

BACKGROUND OF THE INVENTION

Oral solid dosage forms for biologically active agents have beenprepared using various techniques that have been used to combine apowdered biologically active agent substance with a diluent and to formthat mixture into a physical form that is suitable to make powder filledcapsules, compressible particles for making tablets or coatableparticles that are adapted for controlled release of active substancesusing matrix forming additives or membrane based controlled releasecoatings. As used herein, the term “biologically active agent” is usedto include pharmaceutical compounds, pharmaceutical compositions,vitamins and nutrients.

The prior art has used various wet granulation, dry granulation,fluidized-bed, extrusion-spheronization and direct compressiontechniques to prepare particles in the form of granules or pellets formaking solid dosage forms. In addition, spray-drying and spraycongealing techniques have been used to form these types of particles.

The use of fluidized beds has been based on the use of top-spray orbottom-spray techniques using a Wurster air suspension column or atangential-spray in rotary fluid-bed coater/granulator. Apparatus whichhave been used for coating and/or making pellets are described in U.S.Pat. No. 4,895,733; U.S. Pat. No. 5,132,142 and U.S. Pat. No. 6,354,728all of which are incorporated by reference. South African patent20000169 describes certain pharmaceutical pelleted formulations whichcontain up to 90 wt. % of a pharmaceutically active ingredient which aremade by conventional spheronization techniques.

As used herein the term “pellet” means a substantially sphericallyshaped particle having a aspect ratio (a ratio of the length of thepellet divided by the width found at an angle of 90° in respect to thelength) which is less than about 1.4, more preferably less than about1.3, even more preferably less than about 1.2, especially preferablyless than about 1.1, and most preferably less than about 1.05.

In one aspect, the present invention comprises the use of a rotatingdevice that propels the powder particles onto a tangentially arrangedsurface which causes the powder particles to roll on said tangentiallyarranged surface. This process results in pellets having a controlleddensity, for instance highly dense pellets. These pellets may beformulated to have matrix controlled release properties or other typesof release properties depending on the excipients which are employed.The pellets may be: adapted to contain high levels of biologicallyactive agents, i.e. more than 90 wt %, such as more than 95 wt % and inparticular more than 99 wt % and even more than 99.9 wt % of abiologically active agent in each pellet; pellets that are directlymanufactured with a narrow size distribution without the need to carryout any substantial separation step and pellets that have multiplebiologically active agent and/or rate release controlling coatings whichwill provide for controlled release of the active agents and/or physicalseparation of incompatible agents that are advantageously administeredin combination. The pellet may comprise sustained release, pulsatilerelease, enteric release, immediate release or a combination of theserelease characteristics. In addition, the present invention providesnovel processing methods which can optionally be used to reduce oreliminate the use of organic solvents, can produce smaller particles,can reduce the number of process steps and increase the total throughputper operating unit due to greatly reduced processing cycles.

SUMMARY OF THE INVENTION

The invention provides novel pellets adapted for biologically activepreparations and a novel process for preparing said pellets. The pelletscomprise a core and optionally one or more than one layer surroundingthe core. The core and/or at least one layer is formed from powderparticles.

The process of the invention comprises contacting of powder particles,adhering them to each other and compacting said adhered particles by arolling movement.

The process of the invention comprises feeding powder particles into adevice suitable for contacting and adhering said particles. According toone embodiment, the process may be started by feeding powder. In thiscase, pellet cores are formed from said powder particles. Powderparticles are brought into contact such that some of the contacts leadto an adherence of particles to one another. It is usually preferred touse a pharmaceutically acceptable liquid in conjunction with the initialstep of forming a pellet from a powder.

The particles may adhere to each other due to inherent properties of thematerial forming the particles. Powder particles will adhere to oneanother if they are sufficiently tacky. For some materials, this willdepend on the temperature. Alternatively, the adherance of the powderparticles may be enhanced by a pharmaceutically acceptable liquid,optionally comprising a binder.

In accordance with another embodiment, the process is carried out in thepresence of preformed pellets, which are designated as cores. Such coresmay be homogenous or may have an inner structure. Structured corescomprise cores made from different materials, arranged for instance in alayered form, as well as cores having zones of different densities. Thecores may be prepared by the process of the invention. However, it isalso possible to use cores formed by any other technique.

If the process of the invention is carried out in the presence of cores,the cores will be coated with a layer which is formed from powderparticles. The cores are brought into contact with powder particlesunder such conditions that will cause the powder particles to adhere tothe surface of the cores. Further powder particles are then contactedwith powder particles which are already adhered to the surface of thecores to form what may be characterized as a further layer of powderparticles, essentially as described above. In this way, a layer frompowder particles surrounding the core is formed.

According to the invention, during both the formation of cores frompowder particles and the coating of cores with a layer formed frompowder particles, the particles are being formed into a compacted ordensified layer which is usually more compact or dense than the startingproduct (i.e. has a higher bulk density).

The process of the present invention may be carried out in a rotatingdevice that propels the powder particles onto a tangentially arrangedsurface which causes the powder particles to roll on said tangentiallyarranged surface and adhere to other particles thus forming pellets asthe particles roll on the tangential surface. The rolling movement onthe tangential surface is believed to result in a compacting force whichis exerted on the adhering particles during the rolling movement.

The invention provides a process for making pellets adapted forbiologically active preparations, comprising a core and optionally oneor more layers surrounding said core, wherein said core and/or at leastone of said layers is formed by contacting powder particles, adheringthem to each other and compacting said adhered particles by a rollingmovement, wherein the degree of densification is controlled by theenergy uptake during the rolling movement.

In order to bring the pellets being formed into a rolling movement,kinetic energy has to be supplied to them. This can be achieved bymoving, e.g. rotating, a moveable, e.g. rotatable, part of a suitabledevice with which the pellets being formed are in contact. Energytransfer between the moving part of the device and the pellets beingformed will be based on frictional forces leading to a rolling movementof the pellets on surfaces of the device.

A preferred device comprises a rotor and a chamber wherein said rotor islocated. On rotation of said rotor, the pellets being formed move in anoutward direction on said rotor. Ultimately, the pellets come intocontact with an inner wall of said chamber which is arranged to receivethe outwardly moving pellets tangentially so that the pellets will beginto roll as they contact the inner wall of the chamber.

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The preferred device also contains mechanical guide means arranged abovesaid rotor such that the pellets being formed, after leaving said rotor,are guided back onto said rotor. Thus, the pellets being formed are putinto circulation within the device. This allows the pellets being formedto repeatedly come into contact with powder particles fed and optionallywith a pharmaceutically acceptable liquid. Thereby powder particles mayadhere to the pellets being formed so that the pellets grow. Theadhering powder particles are then subjected to a densification when thepellets undergo a rolling movement, e.g. on one of the surfaces of thedevice including the guide means. Because of the circulation of thepellets being formed in the device the densification process iscontinuously occurring as the powder is built up on the pellets.

An especially preferred device for carrying out the process of theinvention is disclosed in U.S. Pat. No. 6,354,728. The use of thisdevice offers the advantage of a particularly effective rolling movementof pellets in a concussion free manner. In this way, damaging thepellets being formed can be avoided. On the other hand, an effectiveuptake of energy can be achieved.

In addition to rolling on surfaces of the device in which the process iscarried out, such as on the rotor surface, the inner wall of the chamberand the surface of the mechanical guide means, the rolling movement alsoinvolves rolling interactions within the bed of pellets being formed.These interactions are based on the spin of the pellets being formed.During the rolling movement of the pellets being formed on surfaces ofthe device used for carrying out the process, the pellets acquire aspin. A pellet being formed which rolls on surfaces of the device willtransfer part of its spin to pellets in direct contact with it. Thus,even pellets which are, during a particular phase of the process, not indirect contact with a surface of the device, will perform a rollingmovement, more precisely a rolling movement relative to other pellets,contributing to the densification of the powder particles.

Thus, it is preferable to carry out the process in such a manner that atleast during a part of the processing time an individual pellet beingformed comes into intimate contact with other pellets being formed. Thisrequires the quantity of pellets processed in one batch to be sized toprovide a sufficient number of intimate contacts with other pellets inorder to cause the final pellets to have the desired properties.Generally, the apparatus that is used in the practice of the inventionshould be operated with an initial load of 25 to 100% of the volumecapacity of the rotor. In any event, the apparatus should be operatedwith a sufficient load of pellets that individual pellets arecontinuously contacted with other pellets.

The interactions of the pellets with surfaces of the device and witheach other, as the pellets are formed, results in the application of ahigh shearing 0force on the pellets. It is believed that in this way,agglomeration of pellets with formation of unwanted lumps is avoided andthe pellets formed have a spherical shape and a narrow particle sizedistribution.

Furthermore, it has now surprisingly been found that the degree ofdensification of the powder particles fed can be controlled by theenergy uptake during the rolling movement. A larger energy uptake leadsto a higher degree of densification.

The energy uptake can be measured as the proportion of the energysupplied to the device in which the process is carried out that is usedto supply energy to the pellets being formed. This proportion of theenergy corresponds to the energy supplied which is not consumed by thedevice itself. The energy uptake may be determined by monitoring theconsumption of energy that is required to operate the apparatus. Forexample, the total electrical energy consumed less frictional losses dueto the operation of the empty apparatus may be used to estimate thetotal energy uptake.

The energy supplied to the pellets being formed, for instance byrotating a rotor in a device containing the pellets, is taken up by thepellets as kinetic energy and as potential energy. This energy taken upis available for the rolling movement of the pellets. During the rollingmovement, energy is used for densification of adhering powder particles.

If the rotation of a rotor is used to supply kinetic energy to thepellets being formed, the energy supply can be varied by varying therotor speed. The rotor speed is a process parameter that can be variedto affect the velocity at which the pellets are moved during processing.

If other factors discussed below are kept constant, a higher rotor speedmeans a higher energy supply to the pellets being formed.

The density and the rate at which a biologically active agent isreleased from the pellets may be controlled by modifying the rotor speedwhich has a direct effect on the radial velocity at which the pelletsmove during processing. The rate of release may also be controlled bythe use of other techniques as disclosed herein. The selected rotorspeed will impart a radial velocity to the pellets which has been foundto affect the density of the final pellet. Generally, it has been foundthat rotor speed that impart a radial velocity (measured at the tip ofthe rotor) of about 12-30 meters/second, will in the case of mostbiologically active materials, produce a pellet having a higher densityand a slower release rate of the biologically active material ascompared to similar pellets made using a lower radial velocity. It hasbeen observed that a rotor speed which induces a radial velocity of from3-10 or more preferably from 4-7.5 meters/second will result in pelletswhich are less dense that the pellets which are produced using a higherradial velocity, i.e. 12-30 meters/second. The pellets containing abiologically active material which are made using a low radial velocitywill generally show a release rate that is more rapid than pellets madewith the same biologically active ingredient and the same excipients atthe same radial velocity.

When biologically active materials are made into pellets according tothe invention by using a high radial velocity, the release rates areretarded to a greater extent as compared to the release rates ofpellets, made from the same materials, which are made in the sameapparatus using conditions which impart a low radial velocity to thepellets. This effect is very pronounced when water insolublebiologically active materials are utilized in the manufacture ofpellets.

As disclosed herein, the invention contemplates feeding, a portion ofthe powder used to make the pellet, in the form of a dry powder as thefinal or terminal step in the formation of the pellets. A terminal stepof feeding the dry powder may be used to further modify the releaseproperties of the biologically active material from pellets preparedaccording to the invention. As detailed in the examples prepared below,the pellets produced using a lower radial velocity will have a slowerrelease rate, of the biologically active material, (from 20 to 40%slower at one in the case of ibuprofen) as compared to pellets madewithout the use of dry powder in the terminal step. The use of a drypowder feed in a terminal step for pellet formation where the pelletsare produced using a high radial velocity is minimal (5-10% slower atone hour in the case of chlorpheniramine.

Release rates may be determined in a USP 23, Type II dissolutionapparatus using water as a dissolution media. at 37° C. at a stirringspeed of 100 rpm.

In general, it is believed that pellets made of water insoluble drugswill exhibit the greatest degree of release rate reduction when madeusing high radial velocities in the process of the invention.

The energy uptake does not only depend on the radial velocity of thepellets which is induced by a particular rotor speed, but also on otherfactors. One such factor is the construction or geometry of the deviceused to carry out the process. If a device such as disclosed in U.S.Pat. No. 6,354,728 is used, the energy uptake can be influenced by thenumber of guide vanes contained in the device.

The energy uptake will also depend on the load of the device, i.e. onthe total amount of material contained in the device. The larger theweight of the material contained in the device, the larger are thecompressive forces exerted on individual pellets due to the weight.

At a constant rotor speed in the same apparatus, the energy uptake willbe higher for a higher load. This has to be taken into consideration forthe control of the degree of densification since the load of the devicewill usually vary during the process of the invention. Making pelletswill require feeding of material, such as powder particles andoptionally a pharmaceutically acceptable liquid, so that the load willincrease. If at least during a part of the processing time, a gas issupplied to remove solvent, this will tend to decrease the load orreduce the increase if other materials are simultaneously fed to theapparatus.

The energy uptake can further be adjusted by feeding a gas, such as airunder ambient conditions, through the bed of the pellets being formed.This will be of particular relevance if the process is carried out at afairly high loading of the capacity of the apparatus.

An apparatus suitable for carrying out this embodiment of the process ofthe invention is disclosed in U.S. Pat. No. 6,354,728. This devicecomprises a rotor located in a chamber such that an annular gap existsbetween the rotor and the inner wall of said chamber. Alternatively orin addition, the rotor may contain openings in its surface allowing agas to pass through.

The gas stream, through the openings in the rotor, may be directed suchthat forces acting on the pellets being formed are reduced or increased.For instance, a gas may be led through openings in the rotor from belowto reduce interactions between pellets and the rotor surface as well asamong the pellets. This will reduce the densification of adhering powderparticles. The quantity and flow rate of the gas which is passed throughthe bed of the pellets should not result in a significant fluidizationof the pellet bed.

The degree of densification of the powder particles will also beinfluenced by the composition of the pellets being formed. One aspect ofthe composition of the pellets being formed is their liquid content. Ahigher liquid content will generally lead to a higher plasticityallowing a more effective densification. However, it has to be notedthat, by the process of the invention, the degree of densification canbe varied for a given composition by regulating the energy uptake of thepellets being formed when these pellets are subjected to a rollingmovement, as described above.

The degree of densification of the powder particles comprised in thepellets made by the process of the invention may be determined by theabsolute porosity of the formed pellet or layer. A high porositycorresponds to a low degree of densification, and vice versa.

The porosity may be visualized by microscopic techniques, for instanceby scanning electron microscopy. Alternatively, the porosity may bedetermined by mercury intrusion.

The degree of densification will also be reflected in the density of thepellets prepared. A higher degree of densification leads to a higherdensity. The achieved absolute porosity, i.e. the percentage of thetotal void space with respect to the bulk volume, may vary between 0.5and 30%. Preferably, the absolute porosity has a value of from 1 to 20%,more preferably of from 1 to 10%, and especially from 2 to 10%.

In a preferred embodiment, the invention provides a spherically shapedpharmaceutical pellet, comprising a core and optionally at least one ormore layers surrounding said core, wherein said core and/or at least oneof said layers is formed from pellets of a powder adhering to eachother, wherein the degree of densification of said particles has apre-determined value. This profile is expressed in terms of the absoluteporosity of the core and/or at least one of said layers formed frompowder particles and has a va98lue of 0.5 to 30%, preferably 1 to 20%and more preferably 2-10%.

Preferably, the pellets have at least one layer formed from particles ofa powder adhering to each other and in certain embodiments may have twoor more layers adhering to one another.

The pellets may be made in such a manner that the degree ofdensification is such that a gradient of the degree of densification ina radial direction is achieved or separate concentric zones havingvarying levels of densification may be formed on each pellet, either inthe core or in one or more layers. The degree of densification may becontrolled so that at least one layer has a density that is lower thanthe bulk density of the starting powder.

Generally the pellets according to the invention will have a diameter offrom 0.01 to 5 mm, such as from 0.1 to 2.5 mm. The layer or layers willeach have a layer thickness of from 0.005 to 2.5 mm, such as from 0.05to 1.25 mm. The pellets prepared according to the invention have anarrow particle size distribution such that a maximum of 20% by weightof the pellets have a diameter deviating from the average diameter ofall by more than 20%. Preferably, a maximum of 10% by weight of thepellets have a diameter deviating from the average diameter of all, bymore than 20%. Further preferably, a maximum of 20% by weight of thepellets have a diameter deviating from the average diameter of allpellets by more than 10% by weight. An especially preferred pelletproduct has a particle size distribution such that a maximum of 10% byweight of the pellets have a diameter deviating from the averagediameter of all pellets by more than 10% by weight. All pervents byweight are based on the total weight of the pellets.

If desired, the pellets may be made from a core which is notsubstantially spherical.

A further embodiment of the pellet of the invention may comprise a corefor a pharmaceutical dosage form, said core having an inner and an outerzone, said inner zone comprising a biologically active agent and saidouter zone comprising a layer which is formed by applying to said innerzone, a substantially dry, free flowing inert powder which forms anon-tacky surface when placed in contact with water. An example of anon-tacky surface is the surface of microcrystalline cellulose which iswetted with water. The free flowing powder is used to prevent thepellets from sticking to one another or to the apparatus.

The invention also provides a process for making pharmaceutical pelletshaving a core with an inner and an outer zone as described hereinwherein the core or at least one of said layers is formed by (a)contacting powder particles, adhering them to each other and compactingsaid adhered pellets by a rolling movement, wherein the degree ofdensification is controlled by the rolling movement; and (b) feeding asufficient amount of a substantially dry, free flowing inert powderwhich forms a non-tacky surface when placed in contact with water toprovide on said particles an outer zone comprising a layer formed fromsaid substantially dry, free flowing inert powder.

A preferred embodiment of the invention provides a process of preparingpellets by:

(a) forming a powder mixture which comprises a binder and a biologicallyactive agent;

(b) feeding said powder mixture which is optionally pre-wetted with from0-60 wt % of a pharmaceutically acceptable liquid diluent, based on thetotal weight of the powder mixture and the pharmaceutically acceptablediluent, to an operating apparatus which comprises a rotor chamberhaving an axially extending cylindrical wall, means for passing airthrough said chamber from the bottom, spray means for feeding a liquidinto said chamber, a rotor which rotates on a vertical rotor axis, saidrotor being mounted in said rotor chamber, said rotor having a centralhorizontal surface and, in at least the radial outer third of saidrotor, the shape of a conical shell with an outward and upwardinclination of between 10° and 80°, said conical shell having acircularly shaped upper edge which lies in a plane which isperpendicular to the rotor axis, feed ports for introducing saidpowdered excipient, a plurality of guide vanes having an outer endaffixed statically to said cylindrical wall of said rotor chamber abovea plane formed by the upper edge of said conical shell of said rotor andan inner end which extends into said rotor chamber and is affixedtangentially to said cylindrical wall of said rotor chamber and having,in cross-section to the rotor axis, essentially the shape of an arc of acircle or a spiral, such that said powdered product which is circulatedby kinetic energy by said rotor under the influence of kinetic energy,moves from said rotor to an inside surface of said guide vanes beforefalling back onto said rotor;(c) rotating said rotor, while feeding air and spraying apharmaceutically acceptable liquid into said rotor chamber for asufficient amount of time to form solid pellets having a desireddiameter; and(d) feeding a sufficient amount of a substantially dry, free flowinginert powder which forms a non-tacky surface when placed in contact withwater to provide on said pellets an outer zone comprising a layer formedfrom said substantially dry, free flowing inert powder.

Accordingly, it is a primary object of the present invention to providenovel pellets which are useful for the delivery of biologically activeagents.

It is also an object of the invention to provide novel pellets which cancontain more than 99 wt % of an active biological agent, such as apharmaceutical.

It is also an object of the invention to provide particles or pelletswhich have matrix release characteristics.

These and other objects of the invention will become apparent from theappended specification.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a scanning electron microscope (SEM) photograph which shows across-sectional view of a pellet of Example 1.

FIG. 2 is a scanning electron microscope (SEM) photograph which shows across-sectional view of a pellet of Example 2.

FIG. 3 is a scanning electron microscope (SEM) photograph which shows across-sectional view of a pellet of Example 3.

FIG. 4 is a scanning electron microscope (SEM) photograph which shows across-sectional view of a pellet of Example 4.

FIG. 5 is a photograph of a magnified view of the gross morphology ofthe pellets of Example 5.

FIG. 6 is a scanning electron microscope (SEM) photograph which shows across-sectional view of a pellet of Example 6.

FIG. 7 is a photograph of a magnified view of the gross morphology, ofthe pellets of Example 7.

FIG. 8A is a scanning electron microscope (SEM) photograph of across-sectional view of a pellet of Example 8 made using a low rotorspeed.

FIG. 8B is a scanning electron microscope (SEM) photograph of across-sectional view of a pellet of Example 8 made using a high rotorspeed.

FIG. 9 is a scanning electron microscope (SEM) photograph which shows across-sectional view of a pellet of Example 9.

DETAILED DESCRIPTION OF THE INVENTION

The pellets of the invention are typically prepared using an apparatuswhich propels particles against a tangentially arranged inner wall insuch a manner that a rolling motion is imparted to the moving pellets. Aliquid is fed into an apparatus such as the apparatus disclosed in U.S.Pat. No. 6,449,869 which is adapted to allow for the introduction ofpowder during the operation of the apparatus. In one embodiment of theinvention, the process of the invention involves the introduction of apowder as a final step in the process in order to control and/orterminating pellet growth as well as assisting in the drying, roundingand smoothing of the pellets. The preferred apparatus is described inU.S. Pat. No. 6,449,869 and U.S. Pat. No. 6,354,728, both of which areincorporated by reference.

In one embodiment, the pellets of the invention, have an inner zonewhich has a structure that results from the application of a liquid to apowder in a particle stream under drying conditions. The liquid causessolid bridges to form and grow until a pellet having a desired size isobtained. At that point, the outer zone of the pellet is formed byfeeding dry powder to the tumbling bed of pellets in order to cause thepellets to grow to their selected final dimension as well as to dry andsmooth the pellets into a highly uniform and highly spherical product.

When the biologically active material is a pharmaceutical, it may be anyphysiologically or pharmacologically active substance that produces alocal or systemic effect, in animals, including warm-blooded mammals,humans and primates

The pharmaceutically acceptable liquid which is used in the formation ofthe pellets may comprise one or more components selected from the groupconsisting of biologically active ingredients, binders, diluents,disintegrants, lubricants, flavoring agents, coloring agents,surfactants, anti-sticking agents, osmotic agents, matrix formingpolymers, film forming polymers, release controlling agents and mixturesthereof, in dissolved, suspended or dispersed form. Generally, onlyselected components will be employed to achieve the desired result for agiven formulation. The particular formulation will determine if, whenand how the listed components are added.

The process of the invention also includes the introduction, of a powderinto a moving stream of partially formed pellets, as a means ofcontrolling the growth of the pellets as well as assisting in therounding and smoothing of the pellets.

The active pharmaceutical that can be delivered includes inorganic andorganic compounds without limitation, including drugs that act on theperipheral nerves, adrenergic receptors, cholinergic receptors, nervoussystem, skeletal muscles, cardiovascular system, smooth muscles, bloodcirculatory system, synaptic sites, neuroeffector junctional sites,endocrine system, hormone systems, immunological system, reproductivesystem, skeletal system, autacoid systems, alimentary and excretorysystems, inhibitory of autocoid systems, alimentary and excretorysystems, inhibitory of autocoids and histamine systems. The active drugthat can be delivered for acting on these recipients includeanticonvulsants, analgesics, anti-inflammatories, calcium antagonists,anesthetics, antimicrobials, antimalarials, antiparasitic,antihypertensives, antihistamines, antipyretics, alpha-adrenergicagonist, alpha-blockers, biocides, bactericides, bronchial dilators,beta-adrenergic blocking drugs, contraceptives, cardiovascular drugs,calcium channel inhibitors, depressants, diagnostics, diuretics,electrolytes, hypnotics, hormonals, hyperglycemics, muscle contractants,muscle relaxants, ophthalmics, psychic energizers, parasympathomimetics,sedatives, sympathomimetics, tranquilizers, urinary tract drugs, vaginaldrugs, vitamins, nonsteroidal anti-inflammatory drugs, angiotensinconverting enzymes, polypeptide drugs, and the like.

Exemplary drugs that are very soluble in water and can be delivered bythe pellets of this invention include prochlorperazine, ferrous sulfate,aminocaproic acid, potassium chloride, mecamylamine hydrochloride,procainamide hydrochloride, amphetamine sulfate, amphetaminehydrochloride, isoproteronol sulfate, methamphetamine hydrochloride,phenmetrazine hydrochloride, bethanechol chloride, methacholinechloride, pilocarpine hydrochloride, atropine sulfate, scopolaminebromide, isopropamide iodide, tridihexethyl chloride, phenforminhydrochloride, methylphenidate hydrochloride, cimetidine hydrochloride,theophylline cholinate, cephalexin hydrochloride, oxybutyninhydrochloride and the like.

Exemplary drugs that are poorly soluble in water and that can bedelivered by the particles of this invention include diphenidol,meclizine hydrochloride, omeprazole prochlorperazine maleate,phenoxybenzamine, thiethylperzine maleate, anisindone, diphenadione,erythrityl tetranitrate, digoxin, isofluorophate, acetazolamide,methazolamide, bendro-flumethiazide, chlorpropamide, tolazamide,chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin,methotrexate, acetyl sulfisoxazole, erythromycin, progestins,progestational, corticosteroids, hydrocortisone hydrocorticosteroneacetate, cortisone acetate, triamcinolone, methyltestosterone, 17beta-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether,prednisolone, 17 betahydroxyprogesterone acetate, non-progesterone,norgesterel, norethindrone, norethisterone, norethiederone,progesterone, norgesterone, norethynodrel, and the like.

Examples of other drugs that can be formulated according to the presentinvention include aspirin, indomethacin, naproxen, fenoprofen, sulindac,indoprofen, nitroglycerin, isosorbide dinitrate, timolol, atenolol,alprenolol, cimetidine, clonidine, imipramine, levodopa,chloropromazine, methyldopa, dihydroxyphenylalamine, pivaloyloxyethylester of alpha-methyldopa hydrochloride, theophylline, calciumgluconate, ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol,zomepirac, ferrous lactate, vincamine, diazepam, phenoxybenzamine,diltiazem, milrinone, captopril, madol, propranolol hydrochloride,quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen,fluprofen, tolmetin, alolofenac, mefanamic, flufenamic, difuninal,nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine,lidoflazine, tiapamil, gallopamil, amlodipine, mioflazine, lisinolpril,enalapril, captopril, ramipril, endlapriate, famotidine, nizatidine,sucralfate, etintidine, tertatolol, minoxidil, chlordiazepoxide,chlordiazepoxide hydrochloride, diazepam, amitriptylin hydrochloride,impramine hydrochloride, imipramine pamoate, enitabas, buproprion, andthe like.

Other examples of biologically active materials include water solublevitamins such as the B Vitamins, Vitamin C and the oil soluble vitaminssuch as Vitamin A, D, E and K. Neutraceuticals such as chondroitin,glucosamine, St. John's wort, saw palmetto and the like may also beformed into pellets according to the present invention.

In the case of pellets having an inner and an outer zone, the inner zoneof the pellets may comprise, depending on the properties of thebiological agent, from 0.1-99 wt % or from 3 to 90 wt % or from 5 to 60wt % of a biologically active agent, based on the total weight of thepellet of one or more pharmaceutically acceptable binders and/ordiluents based on the weight of the pellet. Suitable binders for use inthe invention include those materials that impart cohesive properties tothe powdered biologically active material when admixed dry or in thepresence of a suitable solvent or liquid diluent. These materialscommonly include starches such as pregelatinized starch, gelatin, andsugars such as sucrose, glucose, dextrose, molasses and lactose. Naturaland synthetic gums include acacia, sodium alginate, extract of Irishmoss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, microcrystalline cellulose,polyvinylpyrrolidone e.g. povidone U.S.P K30, Veegum, and larcharabogalactan. Binders are used in an effective amount, e.g. 1 to 10 wt%, based on the total weight of liquid and binder to cause a sufficientdegree of agglomeration of the powders that stable particles are rapidlyformed.

An outer zone may be formed by applying to the inner zone, a powderwhich comprises a substantially dry, free flowing inert powder whichforms a non-tacky surface when placed in contact with water. Examples ofsuch free flowing inert powders include water soluble and waterinsoluble materials. Examples of useful materials includemicrocrystalline cellulose, dicalcium phosphate, calcium sulfate, talc,an alkali metal stearate, silicon dioxide and calcium carbonate.

The powder which comprises a substantially dry, free flowing inertpowder, may also include an active biological agent. For example, aparticle having an outer zone formed from a substantially dry, freeflowing inert powder and a biological agent, may contain, depending onthe properties of the biological agent, from 0.1-99 wt % or from 3 to 90wt % or from 5 to 60 wt % of a biologically active agent, based on thetotal weight of the pellet. In certain cases, it may be convenient toset aside from 5 to 35 wt %, preferably 10 to 25 wt % based on theweight of the total amount of the biological agent and the binder, priorto feeding the initial charge of binder and biological agent to theapparatus. The powder which is set aside may be used to form the outerzone of the pellets in the last stage of the process. This will resultin the pellet having a homogeneous formulation but will still result inthe formation of inner and outer zones having different densities.

Other additives that may be used in the pellet of the invention includediluents, lubricants, disintegrants, coloring agents and/or flavoringagents. The pellets may have a homogeneous or a heterogeneous core. Thehomogenous core may be made from one or more biologically active agentswhich may be homogeneously blended or may be applied as discrete layers.Heterogeneous cores will comprise a base which may be an inorganic ororganic substrate to which concentric layers are applied using theprocess of the invention as described herein. The substrate may comprisean inorganic salt such as calcium phosphate or a non-pareil sugar-starchsphere or a microcrystalline cellulose seed.

In the case of a homogeneous or a heterogeneous core, a plurality oflayers of biologically active materials, inert materials, or releasecontrolling layers may be applied depending on the desired biologicaleffect.

The pellets according to the invention may be made by using an apparatusthat is described in U.S. Pat. No. 6,354,728. That apparatus comprises arotor chamber having an axially extending cylindrical wall, means forpassing air through said chamber from the bottom, spray means forfeeding a liquid into said chamber, a rotor which rotates on a verticalrotor axis, said rotor being mounted in said rotor chamber, said rotorhaving a central horizontal surface and, in at least the radial outerthird of said rotor, the shape of a conical shell with an outward andupward inclination of between 10° and 80°, said conical shell having acircularly shaped upper edge which lies in a plane which isperpendicular to the rotor axis, feed ports for introducing saidpowdered excipient, a plurality of guide vanes having an outer endaffixed statically to said cylindrical wall of said rotor chamber abovea plane formed by the upper edge of said conical shell of said rotor andan inner end which extends into said rotor chamber and is affixedtangentially to said cylindrical wall of said rotor chamber and having,in cross-section to the rotor axis, essentially the shape of an arc of acircle or a spiral, such that said powdered product which is circulatedby kinetic energy by said rotor under the influence of kinetic energy,moves from said rotor to an inside surface of said guide vanes before itfalls back onto said rotor.

When the desired pellet size is substantially achieved, it is preferredto feed dry powder to the apparatus and the apparatus is allowed to runfor a period of 3 to 15 minutes, and preferably 5 to 10 minutes tocomplete the formation of the pellets.

It is also contemplated that some additional drying at a temperature offrom about 30 to 100° C., and preferably from about 40 to 90° C. untilthe moisture content is from 1 to 10 wt %, based on the total weight ofthe pellets depending on the particular biologically active materialand/or the particular excipients. Drying may be carried out in thepreferred apparatus of the invention for making the pellets or in aseparate dryer such as a fluid bed dryer.

The process is preferably based on the use of a minimal amount of liquidin order to avoid causing substantial swelling or gelation of any matrixforming materials which are placed on the pellet according to theinvention.

The matrix forming material may be any swellable or non-swellablematerial that provides in vitro dissolution rates of a biologicallyactive agent within the narrow ranges required to provide the desiredplasma level of the biologically active agent over a desired intervalwhich is typically 12 to 24 hours. Most matrix forming material willalso provide for the release of the biologically active agent in a pHindependent manner. Preferably the matrix is a controlled releasematrix, although normal release matrices having a coating that controlsthe release of the drug may be used. Suitable water-swellable materialsfor inclusion in a controlled release matrix are

(a) Hydrophilic polymers, such as gums, cellulose ethers, acrylic resinsand protein derived materials. Of these polymers, the cellulose ethers,especially hydroxyalkylcelluloses and carboxyalkylcelluloses, arepreferred. The pellets may contain between 1% and 35 wt % of ahydrophilic or hydrophobic polymer.(b) Digestible, long chain (C₉-C₅₀, especially C₁₂-C₄₀), substituted orunsubstituted hydrocarbons, such as fatty acids, fatty alcohols,glyceryl esters of fatty acids, mineral and vegetable oils and waxes.Hydrocarbons having a melting point of between 25° and 90° C. arepreferred. Of these long chain hydrocarbon materials, fatty (aliphatic)alcohols are preferred. The pellets may contain up to 60% (by weight) ofat least one digestible, long chain hydrocarbon.c) Polyalkylene glycols. The pellets may contain up to 60% (by weight)of at least one polyalkylene glycol.

One particular suitable matrix forming material comprises a watersoluble hydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferablyC₁₄-C₂₂, aliphatic alcohol and, optionally, at least one polyalkyleneglycol.

The hydroxyalkyl cellulose is preferably a hydroxy (C₁ to C₆) alkylcellulose, such as hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC). The nominal viscosity of the HPC or HPMC may bebetween 2,500 and 100,000 (2% w/v sol. at 20° C.) and preferably 5,000to 50,000. The amount of the matrix forming material in the pellet willbe determined, inter alia, by the precise rate of release required. Thismay be done by using conventional release rate testing procedures suchas those described in U.S.P. 23, which testing procedures areincorporated by reference. When the pellets are formulated to contain amatrix polymer, the pellets will contain between 1% and 40 wt. %,especially between 5% and 20 wt. % of HPC or HPMC, based on the totalweight of the pellets.

When forming pellets with water-swellable matrix forming materials, careshould be exercised to prevent the matrix forming materials fromswelling due to prolonged contact with liquid diluents in order toprevent the water-swellable matrix forming material from forming a gelduring the pellet formation step.

Non-swellable matrix forming materials comprise water insoluble,dispersible polymers include the commercially availableacrylic/methacrylic polymers as well as ethyl cellulose. Theacrylic/methacrylic polymers are available under various tradenames suchas Eudragit. These materials are used as non-swellable matrix formingpolymers when they are admixed with biologically active compounds andvarious excipients which are formed into pellets according to thepresent invention. Generally from 1 to 30 wt %, of non-swellable matrixforming polymer, based on the weight of biologically active agent,excipient and non-swellable matrix forming polymer of may be admixed forthe purpose of making a powder which may be formed into pelletsaccording to the invention.

A release rate controlling polymer membrane may be applied to thepellets to provide for sustained release, delayed release, e.g. releasein the small intestine by using a pH sensitive coating such as anenteric coating. Suitable enteric coatings include polymeric entericcoating material. The enteric coatings are “pH dependent” whichdescribes the well known effect of an enteric coating which preventsrelease of the dosage form in the low pH conditions of the stomach butpermits release in the higher pH conditions of the small intestine. Theenteric coating will comprise from 1 to 25 wt % and preferably from 5 to10 wt % of the total weight of the pellets. The enteric coating polymermay be selected from the group consisting of shellac, methacrylic acidcopolymers, (Eudragit S or L) cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetate succinate, cellulose acetate trimellitate and polyvinyl acetatephthalate. Methacrylic acid copolymer, Type B USP/NFXXII which dissolvesat a pH above about 6.0 is preferred. The thickness of the coating isselected to provide the desired release rate depending on the thicknessof the coating and the particular coating.

A commercially available copolymer is Eudragit S100 which is based onmethacrylic acid and methyl methacrylate and has a weight averagemolecular weight of about 150,000. Other auxiliary coating aids such asa minor amount (1-5 wt % based on the active core component and thetotal weight of the final coating) of a plasticizer such asacetyltributyl citrate, triacetin, acetylated monoglyceride, rape oil,olive oil, sesame oil, acetyltriethylcitrate, glycerin sorbitol,diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate,diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate,tributylcitrate, glyceroltributyrate, polyethyleneglycol (molecularweight of from 380 to 420), propylene glycol and mixtures thereof incombination with an antisticking agent which may be a silicate such astalc. An antisticking agent, such as talc may be added in an amountwhich is effective to prevent sticking of the pellets. These componentsmay be added to the methacrylic acid copolymer in combination withappropriate solvents.

A sustained release coated pellet may be coated with a polymericmaterial which will substantially maintain its integrity in the varyingpH conditions of the gastrointestinal tract but is permeable to theparticular biologically active agent which is being formulated. Thesustained release coating is used at a level that is selected to releasethe biologically active agent at a rate that will provide the desired invivo release characteristics that will provide the desired plasmaprofile for the selected biologically active agent. Polymers such asethyl cellulose, cellulose acetate, cellulose acetate butyrate, or anacrylic copolymer which when used in a sufficient amount will cause thecoated pellet to release the biologically active agent after ingestionof the dosage form of the invention. Materials such as Eudragit RS 30D;RS 100; NE 30D; RL 30D or RL 100 may be used to prepare the delayedpulse pellet. One such useful material is an acrylate copolymer whichhas a permeability which is independent of pH. That acrylate copolymeris commercially available as Eudragit RS 30D which is available as a 30wt % aqueous dispersion of copolymers of acrylic and methacrylic acidesters, having a number average molecular weight of 150,000 with a lowcontent of quaternary ammonium groups. Other auxiliary coating aids suchas a minor amount (3-7 wt % based on the total weight of the active corecomponent and the total weight of the final coating) of a plasticizersuch as acetyltributyl citrate, triacetin, acetylated monoglyceride,rape oil, olive oil, sesame oil, acetyl triethylcitrate, glycerinsorbitol, diethyloxalate, diethylmalate, diethylfumarate,dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate,triethylcitrate, tributylditrate, glyceroltributyrate,polyethyleneglycol (molecular weight of from 380 to 420), propyleneglycol and mixtures thereof.

If a disintegrant is employed, it may comprise from 2 to 8 wt. % basedon the total weight of the pellet, of starch, clay, celluloses, algins,gums and cross-linked polymers. Super disintegrants such as cross-linkedcellulose, cross-linked polyvinylpyrrolidone, Croscarmellose sodium,carboxymethylcellulose and the like may also be employed if it desiredto have a rapid release of the biologically active agent.

Conventional osmotic agents include non-toxic inorganic salts such assodium chloride, potassium chloride, disodium phosphate and the like orwater soluble non-toxic organic compounds such as lactose, sucrose,dextrose and the like. Antisticking agents such as talc may be employedto achieve any required result.

The pellets of the invention may be placed in hard or soft gelatincapsules to prepare finished dosage forms suitable for administration toa patient or they may be used to prepare compressed tablets usingsuitable cushioning agents, diluents, binders, disintegrants andlubricants.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Example 1

Chlorpheniramine maleate pellets (10% concentration), were produced atlow rotor speed (300 rpm) which induces a radial velocity of about 4.7meters/second in the pellets as compared to pellets produced at highrotor speed (1000 rpm) which induces a radial velocity of about 15meters/second in an apparatus described in U.S. Pat. No. 6,354,728.

Process Conditions: Low rotor speed:

Formulation:

Chlorpheniramine maleate (CPM) 100 g Microcrystalline cellulose (grade101) 900 g1. Blend CPM and MCC in a plastic bag.2. Prewet CPM/MCC blend with 300 g water in a VG (vertical high sheargranulator).3. Transfer prewetted blend into an apparatus made according to U.S.Pat. No. 6,354,728.4. Set the apparatus controls as follow:

Spray rate 35 g/min

-   -   Four baffles (shallow)    -   Atomization air pressure 30%    -   Rotor speed (low) 300 rpm        5. Spray ˜700-1000 g of water        6. Finish spraying water.        7. Discharge the wet pellets. Dry in a GPCG-1 (granulator dryer)        at a temperature of 80° C. to a moisture content of <3%

FIG. 1 is an SEM of a cross-sectional view of the pellet produced inExample 1.

Analytical Testing:

Dissolution of chlorpheniramine maleate 98.2% from pellets (841-1190micron), using USP dissolution testing at 60 min time point Bulk densityof pellets (841-1190 micron) 0.67 g/cc

Example 2

Formulation:

Chlorpheniramine maleate (CPM) 100 g MCC (grade 101) 900 g1. Blend CPM and MCC in a plastic bag.2. Prewet CPM/MCC blend with 300 g water in a VG.3. Transfer prewetted blend into the apparatus used in Example 1.4. Set the parameter for the apparatus as follow: spray rate 35 g/min.

-   -   Four baffles (shallow)    -   Atomization air pressure 30%    -   Rotor speed (high) 1000 rpm        5. Spray ˜700-1000 g of water.        6. Finish spraying water.        7. Discharge the wet pellets. Dry in a CPCG-1 at a temperature        of 80° C. to a moisture content of <3%.

FIG. 2 is an SEM which shows a cross-sectional view of the pelletproduced in Example 2.

Analytical Testing:

Dissolution of chlorpheniramine maleate 89.5% from pellets(841-1190micron), using USP dissolution testing at 60 min time point Bulk densityof pellets (841-1190 micron) 0.80 g/cc

Pellets produced using low rotor speed (Example 1) and high rotor speed(Example 2) have different physical characteristics (pellet shape, bulkdensity, pellet structure).

The pellets produced using high rotor speed at the stated conditions areirregular in shape (not spherical). These pellets may be used as anintermediate in the preparation of spherical pellets.

Drug release of pellets produced using low rotor speed and high rotorspeed also differ. Chlorpheniramine maleate pellets that were producedusing low rotor speed (Example 1) have lower bulk density (0.67 vs. 0.80g/cc) and higher drug release at 60 min time point (98.2 vs. 89.5%) whencompared to the pellets produced using high rotor speed (Example 2).

Example 3

Formulation:

Chlorpheniramine maleate (CPM) 100 g MCC (grade 101) 900 g

-   1. Blend CPM and MCC in a plastic bag.-   2. Prewet CPM/MCC blend with 300 g water in a VG.-   3. Transfer prewetted blend into the apparatus of Example 1.-   4. Set the parameter for processing as follows: Spray rate 35 g/min    -   Four baffles (shallow)    -   Atomization air pressure 30%    -   Rotor speed (low) 300 rpm-   5. After 600 g water sprayed, change the rotor speed to 1000 rpm,    continue spraying water. Additional amount of water to spray    ˜200-400 g.-   6. Finish spraying water.-   7. Discharge the wet pellets. Dry in a GPCG-1 to moisture of <3%

FIG. 3 is an SEM which shows a cross-sectional view of the pelletproduced in Example 3.

Analytical Testing:

Dissolution of chlorpheniramine maleate 90.4% from pellets (841-1190micron), using USP dissolution testing at 60 min time point Bulk densityof pellets (841-1190 micron) 0.79 g/ccSummary:

The pellets produced using low speed initially and adjusting to highrotor speed during processing (Example 3) have higher bulk density (0.79vs. 0.67 g/cc) and lower drug release (90.4 vs. 98.2%) when compared topellets produced using low rotor speed (Example 1). Surface morphologyof the pellets produced using low speed initially and adjusting to highrotor speed during processing (Example 3) was also smoother than thesurface the pellets produced using low rotor speed (Example 1).

Summary: Effect of Rotor Speed

TABLE 1 Effect of Rotor Speed on Bulk Density and Drug Release ofChlorpheniramine maleate Pellets (10% concentration) Low High Low/HighRotor speed (Ex 1) (Ex 2) (Ex 3) Bulk dens. 0.67 g/cc 0.80 g/cc 0.79g/cc Drug rel. 98.2% 89.5% 90.4% (60 min timepoint)

Example 4

To demonstrate the effect of the powder feeding step, 20% of totalweight of blend was set aside to powder feed at the end of sprayingprocess, process is described below. The pellets are compared to thepellets produced at the same low or high rotor speed, described inExample 1 and Example 2.

Formulation:

Chlorpheniramine maleate (CPM) 100 g MCC (grade 101) 900 g

-   1. Blend CPM and MCC in a plastic bag. Weigh 200 g for powder    feeding.-   2. Prewet CPM/MCC blend with 250 g water in a VG.-   3. Transfer prewetted blend into the apparatus of Example 1.-   4. Set the parameter for processing as follows: Spray rate 35 g/min    -   Four baffles (shallow)    -   Atomization air pressure 30%    -   Rotor speed (low) 300 rpm-   5. Spray ˜700-1000 g of water-   6. Start powder feed at powder feed rate of 40 g/min. Reduce spray    rate to 20 g/min and continue spraying water.-   7. Finish spraying water, finish powder feed.-   8. Discharge the wet pellets. Dry in a CPCG-1 to moisture of <3%

FIG. 4 is an SEM photograph which shows a cross-sectional view of apellet made by the procedure of Example 4.

Analytical Testing:

Dissolution of chlorpheniramine maleate 101.9% from pellets(841-1190micron), using USP dissolution testing at 60 min time point Bulk densityof pellets (841-1190 micron) 0.76 g/cc

Example 5 High Rotor Speed with Powder Feeding Step

Formulation:

Chlorpheniramine maleate (CPM) 100 g MCC (grade 101) 900 g1. Blend CPM and MCC in a plastic bag. Weigh 200 g for powder feeding.2. Prewet CPM/MCC blend with 250 g water in a VG.3. Transfer prewetted blend into the apparatus of Example 1.4. Set the parameter for processing as follows: Spray rate 35 g/min.

-   -   Four baffles (shallow)    -   Atomization air pressure 30%    -   Rotor speed (high) 1000 rpm        5. Spray ˜700-1000 g of water.        6. Start powder feed at powder feed rate of ˜40 g/min.    -   Reduce spray rate to 20 g/min and continue spraying water.        7. Finish spraying water, finish powder feed.        8. Discharge the wet pellets. Dry in a CPCG-1 to moisture of        <3%.

FIG. 5 shows the gross morphology of pellets made by the procedure ofExample 5.

Analytical Testing;

Dissolution of chlorpheniramine maleate from 84.7% pellets (841-1190micron), using USP 23 dissolution apparatus with water at 60 minute timepoint Bulk density of pellets (841-1190 micron) 0.79 g/ccSummary:

The processes without powder feeding step (Example 1 for low rotor speedand Example 2 for high rotor speed) were compared to the processes withpowder feeding step (Example 4 for low rotor speed and Example 5 forhigh rotor speed). Other process parameters were kept constant so thatthe only variable during the two processes is powder feeding step.

Powder feeding step at the end of spraying process improved pelletsshape and surface morphology of pellets for both low and high rotorspeed condition (comparing Example 4 to Example 1 and Example 5 toExample 2). The effect of powder feeding on pellet shape was morepronounced at high rotor speed condition (significantly more sphericalwith powder feeding step—Example 4 compared to Example 2). The surfacemorphology was smoother for the pellet produced using powder feedingstep (Example 4 compared to Example 1.).

Chlorpheniramine release from the pellets was not significantly affectedby powder feeding step at low rotor speed condition (98.2% withoutpowder feeding step vs. 101.9% with powder feeding step). At high rotorspeed condition, pellets produced using powder feeding step has slightlylower drug release at 60 min time point (84.7% vs. 89.5% without powderfeeding step).

Example 6

1.8 kg. of pellets (av. diameter 710-850 microns) that were made frommicrocrystalline cellulose (101) were placed in an apparatus accordingto U.S. Pat. No. 6,354,728. The rotary atomizer was used to spray intothe apparatus a solution of chlorpheniramine maleate (CPM) (0.2 kgdissolved in 0.2 kg. of water at a rate of about 19 g/min. which wasincreased to a rate of about 30 g/min. The radial velocity was 8.9meters/second. After the CPM solution spraying is complete, the processwas continued in the same apparatus by introducing a water spray atabout 30 g/min. and a powder blend of 0.8 kg of carboxypolymethylene(Carbopol 971P) and 0.2 kg of talc (S500) at a rate of approximately30-50 g/min. The water spray rate is increased to about 38 g/min. Thepellets begin to stick to one another and the powder feed and waterspray are stopped and about 230 g of microcrystalline cellulose powder(MCC) is added to the apparatus. Spraying is restarted at a rate ofabout 38 g/min. and the powder blend is fed intermittently withadditional 230 g portions of MCC. The water spray rate is decreased toabout 9 g/min. and all, of the powder blend is fed to the apparatus.

An additional 270 g portion of MCC is fed with a water spray at a rateof about 37 g/min. and the powder is fed at a rate of about 30-50 g/min.After the powder feed is complete, the process is terminated and thepellets are dried in a GPCG-1 fluid bed drier at about 80° C. until thepellets are dried to about a 5 wt % average moisture content based onthe total weight of the pellets.

The average diameter of the pellets was approximately 800 microns.

The pellets were tested to determine the rate at which the CPM wasreleased in a USP 23 Type II apparatus at 37° C. at a paddle speed of100 rpm in water. The results were as follows:

Time % CPM released 0.5 h 26.3 1 hr 29.8 2 hr 34.0 3 hr 44.2 6 hr 55.0 8hr 59.9 12 hr 61.1

FIG. 6 is an SEM photograph which shows a cross-section of a pellet madeby the procedure of Example 6.

Example 7

Pellets were made according to the following procedure:

Ibuprofen 25 (BASF) 3,600 g Polyvinylpyrrolidone (PVP K-30)) 200 g MCC(Vivapor 101) 200 g

The blend was mixed in a VG for 1.5 min. A 1.5 kg portion was segregatedfor later use as a powder feed during the last step of the process. Then2.5 kg of the blended powders were then loaded into an apparatus that isdescribed in U.S. Pat. No. 6,354,728.

Spraying was initiated with water containing 0.1 w % of Tween 80. Thespray rate was 19 g/min. and the initial rotor speed was 475 rpm (8.9meters/sec.) (70%) gradually increasing to 550 rpm (10.4 meters/sec.(80%). After 320 g was sprayed, the spray rate was increased to about 40g/min. which seemed to be too fast. The spray rate was then reduced toabout 29 g/min. When 750 g had been sprayed, it appeared that somepowder had been sucked in through the powder feed port. After 863 g hadbeen sprayed, the spray rate was increased to about 40 g/min. and powderfeeding was started at a rate of about 66 g/min. The liquid spray ratewas decreased to about 29 g/min. Spraying was stopped after 1379 g hadbeen sprayed and all of the powder (1.25 kg) was added and the rotor wasoperated for about 4 minutes after the powder feeding was complete. Thetotal process time was about 50 min. The pellets were dried in a GPCG-1at 55-65° C. until the product temperature was 45° C. The grossmorphology of the pellets is shown in FIG. 7. The average size isapproximately 800 microns.

Example 8

Ibuprofen pellets (10% concentration) that are produced at low rotorspeed (300 rpm) are compared to pellets produced at high rotor speed(1000 rpm).

II

Ibuprofen (IBU) 100 g MCC (grade101) 900 g

1. Blend IBU and MCC in a plastic bag.

2. Prewet IBU/MCC blend with 300 g water in a VG.

3. Transfer prewetted blend into the apparatus of Example 1.

4. Set the parameter for processing as follows: Spray rate 35 g/min.

-   -   i. Four baffles (shallow)    -   ii. Atomization air pressure 30%    -   iii. Rotor speed (low) 300 rpm

5. Spray ˜700-1000 g of water

6. Finish spraying water.

7. Discharge the wet pellets. Dry in a GPCG-1 to moisture of <5%

Analytical Testing:

Dissolution of Ibuprofen from pellets 72.1% (841-1190 micron), using USPdissolution testing at 60 min time point Bulk density of pellets(841-1190 micron) 0.66 g/ccProcess conditions: High rotor speedFormulation:

Ibuprofen (IBU) 100 g MCC (grade101) 900 g

1. Blend IBU and MCC in a plastic bag.

2. Prewet IBU/MCC blend with 300 g water in a VG.

3. Transfer prewetted blend into the apparatus of Example 1. Set theparameter for processing as follows:

-   -   Spray rate 35 g/min.    -   Four baffles (shallow)    -   Atomization air pressure 30%    -   Rotor speed (high) 1000 rpm

4. Spay ˜700-1000 g of water.

5. Finish spraying water.

6. Discharge the wet pellets. Dry in a GPCG-1 to moisture of <5%.

Analytical Testing:

Dissolution of Ibuprofen from pellets 38.6% (841-1190 micron), using USPdissolution testing at 60 min time point Bulk density of pellets(841-1190 micron) 0.80 g/cc

FIG. 8A is a SEM of a cross-section of a pellet made using a low rotorspeed and FIG. 8B is a SEM of a cross-section of a pellet made at highrotor speed.

Summary:

Ibuprofen pellets produced using low rotor speed and high rotor speedhave different physical characteristics (particle shape, bulk density,pellet structure). The pellets produced using high rotor speed are notas spherical as the pellets produced using low rotor speed.

Drug release of pellets produced using low rotor speed and high rotorspeed also differs. Ibuprofen, which is a water insoluble compound,released at significantly slower rate from pellets produced at highrotor speed than from pellets produced at low rotor speed (38.6% vs.72.1%). The bulk density of pellets produced at high rotor speed washigher than that of pellets produced at low rotor speed (0.80 vs. 0.66g/cc). Pellet structure (under scanning electron microscope) was denserfor pellets produced at high rotor speed.

Example 9

Pellets were made using a combination of low and high rotor speeds asfollows:

Formulation:

Ibuprofen (IBU) 100 g MCC (grade 101) 900 g

-   -   1. Blend IBU and MCC in a plastic bag.    -   2. Prewet IBU/MCC blend with 300 g water in a VG.    -   3. Transfer prewetted blend into the apparatus of Example 1.    -   4. Set the parameter for the apparatus of Example 1 processing        as follows:    -   5. Spray rate 35 g/min        -   Four baffles (shallow)        -   Atomization air pressure 30%        -   Rotor speed (low) 300 rpm    -   6. After 600 g water sprayed, change the rotor speed to 1000        rpm, continue spraying water. Additional amount of water to        spray ˜200-400 g.    -   7. Finish spraying water.    -   8. Discharge the wet pellets. Dry in a GPCG-1 to moisture of <5%        Analytical Testing:

Dissolution of Ibuprofen from pellets 60.2%% (841-1190 micron), usingUSP dissolution testing at 60 min time point Bulk density of pellets(841-1190 micron) 0.75 g/cc

FIG. 9 is an SEM of a cross-section of a pellet made according toExample 9.

Summary:

The Ibuprofen pellets produced using low speed initially and adjustingto high rotor speed during processing (Example 9) have higher bulkdensity (0.75 vs. 0.66 g/cc) and lower drug release (60.2% vs. 72.1%)when compared to pellets produced using low rotor speed (Example 8).Surface morphology of the pellets produced using low speed initially andadjusting to high rotor speed during processing was slightly smootherthan the surface the pellets produced using low rotor speed.

Summary: Effect of Rotor Speed

TABLE II.1 Effect of Rotor Speed on Bulk Density and Drug Release ofIbuprofen Pellets (10% concentration) Low rotor speed initially,adjusted to high rotor speed Low rotor speed High Rotor Speed duringprocessing Rotor Speed (Ex. 8) (Ex. 8) (Ex. 9) Bulk density 0.66 g/cc0.80 g/cc 0.75 g/cc Drug release 72.1% 38.6% 60.2% (60 min timepoint)

Example 10

To investigate the effect of powder feeding step, 20% of total weight ofblend was set aside to powder feed at the end of spraying process,process is described below. The pellets are compared to the pelletsproduced at the same low or high rotor speed, described in Example 8.

Formulation:

Ibuprofen (IBU) 100 g MCC (grade101) 900 g

-   -   1. Blend IBU and MCC in a plastic bag. Weigh 200 g for powder        feeding.    -   2. Prewet IBU/MCC blend with 250 g water in a VG.    -   3. Transfer prewetted blend into apparatus of Example 1.    -   4. Set the parameter for processing as follows:        -   Spray rate 35 g/min        -   Four baffles (shallow)        -   Atomization air pressure 30%        -   Rotor speed (low) 300 rpm    -   5. Spray ˜700-1000 g of water    -   6. Start powder feed at powder feed rate of 40 g/min. Reduce        spray rate to 20 g/min and continue spraying water.    -   7. Finish spraying water, finish powder feed.    -   8. Discharge the wet pellets. Dry in a GPCG-1 to moisture of <5%        Analytical Testing:

Dissolution of Ibuprofen from pellets 47.3% (841-1190 micron), using USPdissolution testing at 60 min time point Bulk density of pellets(841-1190 micron) 0.70 g/ccProcess conditions: High rotor speed

Ibuprofen (IBU) 100 g MCC (grade101) 900 g

-   -   1. Blend IBU and MCC in a plastic bag. Weigh 200 g for powder        feeding.    -   2. Prewet IBU/MCC blend with 250 g water in a VG.    -   3. Transfer prewetted blend into the apparatus of Example 1.    -   4. Set the parameter for the apparatus of Example 1 as follow:    -   5. Spray rate 3 5 g/min.        -   Four baffles (shallow)        -   Atomization air pressure 30%        -   Rotor speed {high) 1000 rpm    -   6. Spray ˜700-1000 g of water.    -   7. Start powder feed at powder feed rate of ˜40 g/min. Reduce        spray rate to 20 g/min and continue spraying water.    -   8. Finish spraying water, finish powder feed.    -   9. Discharge the wet pellets. Dry in a GPCG-1 to moisture of <5%        Analytical Testing:

Dissolution of Ibuprofen from pellets 44.9% (841-1190 micron), using USPdissolution testing at 60 min time point Bulk density of pellets(841-1190 micron) 0.77 g/ccSummary:

The processes without powder feeding step for low rotor speed and forhigh rotor speed (Example 8) were compared to the processes with powderfeeding step for low rotor speed and for high rotor speed (Example 10).Other process parameters were kept constant so that the only variableduring the two processes is powder feeding step.

For Ibuprofen, which is a water insoluble compound, effect of powderfeeding step on pellet shape and morphology was not as pronounced as inthe case of Chlorpheniramine maleate which is a water soluble compound.

The effect of powder feeding step on the Ibuprofen release rate was verysignificant. This effect is more distinct for Ibuprofen (water insolublecompound) than Chlorpheniramine maleate (water soluble compound).

At low rotor speed condition, the powder feeding step led to asignificant decrease in Ibuprofen release from pellets (at 60 mintimepoint, 47.3% vs. 72.1% without powder feeding step). The bulkdensity of pellets produced using powder feeding step was slightlyhigher (0.70 g/cc vs. 0.66 g/cc without powder feeding step).

At high rotor speed condition, the powder feeding step led to slightincrease in Ibuprofen release (at 60 min timepoint, 44.9% vs. 38.6%without powder feeding step).

The bulk density of pellets produced using powder feeding step wasslightly lower (0.77 g/cc vs. 0.88 g/cc without powder feeding step).

Dissolution Profiles of Ibuprofen Pellets (prepared at low rotor speed,high rotor speed and low rotor speed with powder feeding).

The Ibuprofen pellets prepared in Example 8 and Example 10 weresubmitted for dissolution testing for 24 hours.

The dissolution profiles are summarized in Table 2.

Dissolution of Ibuprofens from Pellets Prepared at different processconditions High Rotor Low Rotor Speed Time Low Rotor Speed Speed withpowder feed (hours) (Ex. 8) (Ex. 8) (Ex. 10) 0.25 34.2 19.2 24.9 1 72.139.6 49.0 2 94.3 54.2 66.8 4 103.0 71.9 87.6 6 103.1 83.3 98.5 8 103.391.0 101.6 12 103.5 97.5 101.9 18 103.4 97.7 102.2 24 103.7 98.1 102.3Bulk Density 0.66 0.80 0.70 (g/cc)

Using Ibuprofen as an example of a water insoluble compound, it ispossible to produce sustained release drug pellets by controlling theprocess conditions of the invention (low vs. high rotor speed) thataffect density of pellets which in turn affect drug release from thepellets.

The process of the invention allows the process parameters to beadjusted during pellet formation. These adjustments can affect physicalcharacteristics, as well as drug release, of pellets. It is possible toadd additional powder (after core pellets are formed). This addition ofpowder can affect pellets shape, morphology and release of drug from thepellets. The powder feeding step for Ibuprofen pellets, which is a waterinsoluble compound, affected the release rate significantly, especiallyat low rotor speed conditions. It is possible to produce sustainedrelease pellets by varying density of pellets being formed and byaddition of powder during processing.

The invention claimed is:
 1. A process for making solid pellets whichare adapted for use as a pellet core for a dosage form which includes abiologically active agent, said process comprising: (a) providing afirst powder mixture comprising: a biologically active agent; and abinder, an inert powder, or a combination thereof; (b) providing anoperating apparatus comprising: a rotor chamber having an axiallyextending cylindrical wall; means for passing air through said chamberfrom the bottom; spray means for feeding a liquid into said chamber; arotor which rotates on a vertical rotor axis, and which is mounted insaid rotor chamber, where said rotor has: a central horizontal surfaceand, in at least the radial outer third of said rotor, the shape of aconical shell with an outward and upward inclination of between 10° and80°; wherein said conical shell has a circularly shaped upper edge whichlies in a plane which is perpendicular to the rotor axis; feed ports forintroducing a powder; a plurality of guide vanes having: an outer endaffixed statically to said cylindrical wall of said rotor chamber abovea plane formed by the upper edge of said conical shell of said rotor;and an inner end which extends into said rotor chamber and is affixedtangentially to said cylindrical wall of said rotor chamber; whereinsaid plurality of guide vanes have, in cross-section to the rotor axis,essentially the shape of an arc of a circle or a spiral, (c) feedingsaid first powder mixture which is optionally pre-wetted with from 0-60%of a pharmaceutically acceptable diluent, based on the total weight ofthe first powder mixture and the optional pharmaceutically acceptablediluent, to the operating apparatus such that said first powder mixture,which is circulated by kinetic energy by said rotor under the influenceof kinetic energy, moves from said rotor to an inside surface of saidguide vanes before falling back onto said rotor; (d) rotating saidrotor, while feeding air and spraying a pharmaceutically acceptableliquid into said rotor chamber for a sufficient amount of time to formsolid pellets having a desired diameter; and (e) feeding a sufficientamount of a dry second powder which forms a non-tacky surface whenplaced in contact with water to provide on said particles an outer zonecomprising a layer formed from said dry powder, the dry second powdercomprising at least one substance selected from the group consisting of:biologically active agents; binders; and free-flowing inert powders. 2.The process as defined in claim 1; wherein, in step (e), the dry secondpowder has the same composition as the non-wetted first powder mixturethat is fed in step (a).
 3. The process as defined in claim 1; whereinsaid first powder mixture in step (a) comprises a biologically activeagent and an inert powder that is selected from the group consisting ofmicrocrystalline cellulose, dicalcium phosphate, calcium sulfate, talc,an alkali metal stearate, silicon dioxide, calcium carbonate, andmixtures thereof.
 4. The process as defined in claim 1; wherein thefirst powder mixture in step (a) comprises a biologically active agentand an inert powder that is microcrystalline cellulose.
 5. The processas defined in claim 1; wherein the biologically active agent of thefirst powder mixture comprises at least one compound selected from thegroup consisting of vitamins, nutrients, pharmaceuticals, and mixturesthereof.
 6. The process as defined in claim 1; wherein the biologicallyactive agent of the first powder mixture is a pharmaceutically activecompound.
 7. The process as defined in claim 1; wherein, in step (c),the first powder mixture which is pre-wetted with from greater than 0%to 60% of the pharmaceutically acceptable liquid diluent; and whereinthe pharmaceutically acceptable liquid diluent comprises water.
 8. Aprocess for making discrete substantially spherical pellets comprising:(a) providing a first powder mixture comprising: a first biologicallyactive agent; and a binder, an inert powder, or a combination thereof;(b) providing an operating apparatus comprising: a rotor chamber havingan axially extending cylindrical wall; means for passing air throughsaid chamber from the bottom; spray means for feeding a liquid into saidchamber; a rotor which rotates on a vertical rotor axis, and which ismounted in said rotor chamber, where said rotor has: a centralhorizontal surface and, in at least the radial outer third of saidrotor, the shape of a conical shell with an outward and upwardinclination of between 10° and 80°; wherein said conical shell has acircularly shaped upper edge which lies in a plane which isperpendicular to the rotor axis; feed ports for introducing a powder; aplurality of guide vanes having: an outer end affixed statically to saidcylindrical wall of said rotor chamber above a plane formed by the upperedge of said conical shell of said rotor; and an inner end which extendsinto said rotor chamber and is affixed tangentially to said cylindricalwall of said rotor chamber; wherein said plurality of guide vanes have,in cross-section to the rotor axis, essentially the shape of an arc of acircle or a spiral; (c) feeding the first powder mixture, which ispre-wetted with from 5-60% of a pharmaceutically acceptable liquiddiluent, based on the total weight of the first powder mixture and theliquid diluent, to the operating apparatus, such that said first powdermixture, which is circulated by kinetic energy by said rotor under theinfluence of kinetic energy, moves from said rotor to an inside surfaceof said guide vanes before falling back onto said rotor; and (d)rotating said rotor, while feeding air and spraying a pharmaceuticallyacceptable liquid into said rotor chamber for a sufficient amount oftime to form substantially spherical pellets having a desired diameter;and (e) feeding a sufficient amount of a dry second powder which forms anon-tacky surface in contact with water to form an outer layer on saidsubstantially spherical pellets, the dry second powder comprising: asecond biologically active agent, which may be the same as or differentfrom the first biologically active agent; and a binder, a free-flowinginert powder, or a combination thereof.
 9. The process as defined inclaim 8; wherein, in step (e), the dry second powder is added in anamount that is equivalent to 5 to 35 wt. % of the wetted first powdermixture that was initially fed to the apparatus, and the apparatus isallowed to run for a period of time to form said outer layer.
 10. Theprocess as defined in claim 8; wherein said dry second powder includesmicrocrystalline cellulose and optionally comprises one or morecomponents selected from the group consisting of binders, diluents,lubricants, disintegrants, flavors, surfactants, anti-sticking agents,osmotic agents, and mixtures thereof.
 11. The process as defined inclaim 8; wherein the first biologically active compound comprises atleast one compound selected from the group consisting of vitamins,nutrients, pharmaceuticals, and mixtures thereof.
 12. The process asdefined in claim 8; wherein the first biologically active agent is apharmaceutically active compound.
 13. The process as defined in claim 8;wherein the pharmaceutically acceptable liquid diluent is water.
 14. Theprocess as defined in claim 1; wherein, in step (e), the dry secondpowder is added in an amount that is equivalent to 5 to 35 wt. % of theoptionally wetted first powder mixture that was initially fed to theapparatus, and the apparatus is allowed to run for a period of time toform said outer layer.
 15. The process as defined in claim 1; whereinthe spraying of the pharmaceutically acceptable liquid is stopped, afterwhich the dry second powder is fed to the operating apparatus.
 16. Theprocess as defined in claim 8; wherein the spraying of thepharmaceutically acceptable liquid is stopped, after which the drysecond powder is fed to the operating apparatus.